The process of programmed cell death, or apoptosis, is generally characterized by distinct morphological characteristics and energy-dependent biochemical mechanisms. Apoptosis is considered a vital component of various processes including normal cell turnover, proper development and functioning of the immune system, hormone-dependent atrophy, embryonic development and chemical-induced cell death. Inappropriate apoptosis (either too little or too much) is a factor in many human conditions including neurodegenerative diseases, ischemic damage, autoimmune disorders and many types of cancer. The ability to modulate the life or death of a cell is recognized for its immense therapeutic potential. Therefore, research continues to focus on the elucidation and analysis of the cell cycle machinery and signaling pathways that control cell cycle arrest and apoptosis. To that end, the field of apoptosis research has been moving forward at an alarmingly rapid rate. Although many of the key apoptotic proteins have been identified, the molecular mechanisms of action or inaction of these proteins remain to be elucidated. The goal of this review is to provide a general overview of current knowledge on the process of apoptosis including morphology, biochemistry, the role of apoptosis in health and disease, detection methods, as well as a discussion of potential alternative forms of apoptosis.

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Apoptosis: A Review of Programmed Cell Death

A variety of key events in apoptosis focus on mitochondria, including the release of caspase activators (such as cytochrome c), changes in electron transport, loss of mitochondrial transmembrane potential, altered cellular oxidation-reduction, and participation of pro- and antiapoptotic Bcl-2 family proteins. The different signals that converge on mitochondria to trigger or inhibit these events and their downstream effects delineate several major pathways in physiological cell death.

https://science.sciencemag.org/content/sci/281/5381/1309.full.pdf

Mitochondria and apoptosis

The discovery of Toll-like receptors (TLRs) as components that recognize conserved structures in pathogens has greatly advanced understanding of how the body senses pathogen invasion, triggers innate immune responses and primes antigen-specific adaptive immunity. Although TLRs are critical for host defense, it has become apparent that loss of negative regulation of TLR signaling, as well as recognition of self molecules by TLRs, are strongly associated with the pathogenesis of inflammatory and autoimmune diseases. Furthermore, it is now clear that the interaction between TLRs and recently identified cytosolic innate immune sensors is crucial for mounting effective immune responses. Here we describe the recent advances that have been made by research into the role of TLR biology in host defense and disease.

/pdf/the-role-of-pattern-recognition-receptors-in-innate-immunity-39y77tlxza.pdf

The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors

Apoptosis - the regulated destruction of a cell - is a complicated process. The decision to die cannot be taken lightly, and the activity of many genes influence a cell's likelihood of activating its self-destruction programme. Once the decision is taken, proper execution of the apoptotic programme requires the coordinated activation and execution of multiple subprogrammes. Here I review the basic components of the death machinery, describe how they interact to regulate apoptosis in a coordinated manner, and discuss the main pathways that are used to activate cell death.

The biochemistry of apoptosis

https://www.cell.com/cell/pdf/S0092-8674(00)80434-1.pdf

Cytochrome c and dATP-Dependent Formation of Apaf-1/Caspase-9 Complex Initiates an Apoptotic Protease Cascade

Modulator is an endogenous low-molecular-weight regulator of both glucocorticoid and mineralocorticoid receptors as well as protein kinase C. Structural analysis of modulator purified to apparent homogeneity suggests that it is a novel ether aminophosphoglyceride. In this report, we show that modulator inhibits cytosolic human glucocorticoid receptor (GR) complex activation as measured by DNA-cellulose binding. In addition, modulator blocks glucocorticoid-induced nuclear translocation of the GR in intact human leukemic (CEM C-7) cells, as illustrated by immunocytochemical localization. Furthermore, we demonstrate that modulator, by blocking the activation and subsequent translocation of GR, inhibits glucocorticoid-mediated apoptosis, characterized by chromatin condensation, internucleosomal DNA fragmentation, and cell death in glucocorticoid-sensitive CEM C-7 cells. Modulator inhibits glucocorticoid-induced c- myc gene repression and glucocorticoid receptor gene up-regulation. These data suggest that modulator functions to regulate the GR in intact cells as well as in cytosolic preparations. In addition, the inhibition of glucocorticoid-induced programmed cell death by modulator sheds light on the cellular function of modulator as well as on the mechanism by which apoptosis occurs in CEM C-7 cells.

https://cancerres.aacrjournals.org/content/canres/55/3/548.full.pdf

Modulator Inhibits Nuclear Translocation of the Glucocorticoid Receptor and Inhibits Glucocorticoid-induced Apoptosis in the Human Leukemic Cell Line CEM C-7

Apoptosis is a form of programmed cell death (PCD) that plays critical physiological roles in removing superfluous or dangerous cell populations that are unneeded or threatening to the health of the host organism. Although the molecular pathways leading to activation of the apoptotic program have been extensively studied and characterized starting in the 1970s, new evidence suggests that members of the gasdermin superfamily are novel pore-forming proteins that augment apoptosis by permeabilizing the mitochondria and participate in the final stages of the apoptotic program by inducing secondary necrosis/pyroptosis. These findings may explain outstanding questions in the field such as why certain gasdermin members sensitize cells to apoptosis, and why some apoptotic cells also show morphological features of necrosis. Furthermore, the interplay between the gasdermins and apoptosis may also explain why genetic and epigenetic alterations in these genes cause diseases and disorders like cancer and hearing loss. This review focuses on our current understanding of the function of several gasdermin superfamily members, their role in apoptosis, and how they may contribute to pathophysiological conditions.

/pdf/gasdermins-in-apoptosis-new-players-in-an-old-game-3zofvggjbn.pdf

Gasdermins in Apoptosis: New players in an Old Game.

Two FADD-like anti-apoptotic proteins that regulate Fas/TNFR1- or UV-induced apoptosis are disclosed. Nucleotide sequences encoding the proteins are disclosed as are methods of using the nucleic acid molecules and making the proteins. Pharmaceutical compositions and methods of using the same are disclosed. Reagents, kits and methods of identifying compounds that inhibit anit-apoptotic activity of the proteins and methods of identifying compounds that inhibit binding activity of the proteins are disclosed.

Fadd-like anti-apoptotic molecules, methods of using the same, and compositions for and methods of making the same

Purification of the death substrate poly(ADP-ribose) polymerase

Substantially pure interleukin-1 converting enzyme isoforms are disclosed. Pharmaceutical compositions comprising one or more interleukin-1 converting enzyme isoforms are disclosed. Nucleic acid molecules that encode interleukin-1 converting enzyme isoforms, recombinant expression vectors that comprise a nucleic acid sequence that encodes an interleukin-1 converting enzyme isoform, and host cells that comprise recombinant expression vectors that comprise nucleic acid sequences that encode interleukin-1 converting enzyme isoforms are disclosed. Fragments of nucleic acid molecules with sequences encoding interleukin-1 converting enzyme isoform and oligonucleotide molecules that comprise a nucleotide sequence complimentary to fragment of a nucleotide sequence that encodes an interleukin-1 converting enzyme isoform are disclosed. Antibodies which bind to an epitope on interleukin-1 converting enzyme isoforms are disclosed. Methods of identifying inhibitors of ICE isoforms are disclosed.

Emad S. Alnemri

Papers

Modulator Inhibits Nuclear Translocation of the Glucocorticoid Receptor and Inhibits Glucocorticoid-induced Apoptosis in the Human Leukemic Cell Line CEM C-7

Gasdermins in Apoptosis: New players in an Old Game.

Fadd-like anti-apoptotic molecules, methods of using the same, and compositions for and methods of making the same

Purification of the death substrate poly(ADP-ribose) polymerase

Isoforms of human interleukin-1β converting enzyme and methods of using the same